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The safety, efficacy and predictors for HbA1c reduction of sitagliptin in the treatment of Japanese type 2 diabetes
diabetes research and clinical practice 95 (2012) e20–e22
Contents available at Sciverse ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Brief report
The safety, efficacy and predictors for HbA1c reduction of sitagliptin in the treatment of Japanese type 2 diabetes Hajime Maeda a,*, Akira Kubota a, Yasushi Tanaka b, Yasuo Terauchi c, Ikuro Matsuba a ASSET-K Study group a The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3F Kanagawa-ken Sogo Iryo Kaikan, 3-1 Fujimi-cho, Naka-ward, Yokohama-city, Kanagawa 231-0037, Japan b Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa 216-8511, Japan c Department of Endocrinology and Metabolism, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama-city, Kanagawa 236-0004, Japan
article info
abstract
Article history:
We evaluated the efficacy and safety of sitagliptin after 3 months’ treatment in Japanese
Received 26 September 2011
type 2 diabetic patients and examined changes in clinical factors. Baseline HbA1c, PPG, BMI,
Received in revised form
and duration of diabetes may be predictors of HbA1c reduction when using sitagliptin in
1 October 2011
Japanese type 2 diabetic patients. # 2011 Elsevier Ireland Ltd. All rights reserved.
Accepted 10 October 2011 Published on line 3 November 2011 Keywords: Dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin BMI HbA1c
1.
Introduction
This study involved a large number of Japanese type 2 diabetic patients being treated by diabetes specialists at multiple medical centers. The efficacy, safety, and the effects of patient background factors on HbA1c reduction at 3 months after starting treatment were evaluated.
2.
Methods
A total of 1332 patients were enrolled. At baseline and 3 months after starting sitagliptin, body weight, BMI, blood pressure and glycemic control-related markers were measured. Lipids, renal function, and liver function were also examined. To identify clinical factors affecting the efficacy of sitagliptin, multiple regression analyses between the change
* Corresponding author at: HEC Science Clinic, 4-1-4-102 Yokodai, Isogo-ku, Yokohama, Kanagawa 235-0045, Japan. Tel.: +81 45 831 0031; fax: +81 45 8310399. E-mail addresses: [email protected], [email protected] (H. Maeda). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.10.011
e21
diabetes research and clinical practice 95 (2012) e20–e22
Table 1 – Clinical characteristics of 1332 subjects enrolled.
in HbA1c and the patients’ baseline characteristics were performed. Safety was assessed by review of safety evaluations. All analyses were performed using SPSS for Windows. Data are presented as means SD. Statistical significance was defined as p 0.05.
3.
n Age (years) Sex (male/female) Duration of diabetes (years) Smoking (%) Drinking (%) Hypertension (%) Dyslipidemia (%) Diabetic retinopathy (%) Diabetic nephropathy (%) Diabetic neuropathy (%) Medications (%) No other OADs 1 other OAD 2 other OADs 3 other OADs
Results
The patients’ baseline demographic characteristics are shown in Table 1. 20% of all patients were treated with sitagliptin alone, 36% were treated in combination with 1 other drug, 31% were treated in combination with 2 other drugs, and 12% were treated in combination with 3 or more other drugs. With regard to changes in glycemic control after 3 months (Table 2), as compared to baseline, HbA1c decreased from 8.0% at baseline to 7.3% ( p < 0.001), and 1,5-AG increased ( p = 0.004). There were significant decreases in PPG, and in FPG ( p < 0.001). Compared with baseline, no significant weight gain was observed with sitagliptin. At 3 months, both SBP and DBP were reduced from baseline, with mean reductions of 1.2 mmHg. After 3 months, mean LDL cholesterol decreased significantly ( p < 0.001) (Table 2). On multiple regression analysis, taking HbA1c reduction at 3 months as a dependent variable, and age, baseline HbA1c, PPG, BMI, and duration of diabetes as independent variables, baseline HbA1c, baseline PPG, baseline BMI, and duration of diabetes were independently correlated with the HbA1c reduction at 3 months ( p < 0.001). As expected, baseline HbA1c was the strongest predictor. The new finding is that baseline PPG, baseline BMI and the duration of diabetes are weaker but significant predictors of change in HbA1c, showing that sitagliptin is expected to be more effective in patients with higher PPG, lower BMI or with shorter duration of diabetes. Serum creatinine and uric acid increased from baseline to 3 months ( p < 0.001) (Table 2). Adverse events were generally mild to moderate. The most common adverse event
1332 62.9 11.6 751/581 12.0 8.1 23 29 32 36 21 28 26 20 36 31 12
OAD, oral antidiabetic drug.
was hypoglycemia in 40 patients (3%); all reported events were mild. There were no serious side effects, including severe hypoglycemia.
4.
Discussion
In this multicenter collaborative study of Japanese patients treated in clinical practice by diabetes specialists, switching to sitagliptin, or using sitagliptin in combination therapy, achieved significantly improved glycemic control without weight gain. In19.3% of patients on combination therapy with a sulfonylurea, the sulfonylurea dose was reduced. There are few reports of >2 combined drugs [1], but there are several reports about the efficacy, safety, tolerability, and mechanism of action of combination therapy with sulfonylureas [2],
Table 2 – Laboratory data in type 2 DM patients at baseline, 1 month, and 3 months. n HbA1c (% in NGSP units) 1,5-AG (mg/mL) FPG (mg/dL) PPG (mg/dL) Weight (kg) BMI (kg/m2) SBP (mmHg) DBP (mmHg) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) AST (IU/L) ALT (IU/L) g-GTP (IU/L) BUN (mg/dL) Cr (mg/dL) Uric acid (mg/dL) Data are means (SD). ANOVA: vs. 0 m, p < .01. y ANOVA: vs. 0 m, p < .05. z ANOVA: vs. 1 m, p < .01. *
1029 154 165 503 936 861 663 663 438 374 494 386 393 398 360 328 345
0m 8.0 (1.1) 7.8 (5.7) 156.0 (37.2) 195.0 (72.0) 63.8 (13.4) 24.6 (4.3) 128.5 (13.9) 75.0 (10.8) 112.1 (29.1) 57.5 (17.5) 157.3 (105.6) 25.0 (16.1) 27.2 (21.0) 48.5 (61.4) 16.5 (6.7) 0.74 (0.23) 5.1 (1.3)
1m
3m *
7.6 (1.0) 8.6 (6.0)* 135.7 (29.0)* 165.7 (56.6)* 63.9 (13.5) 24.7 (4.3) 127.7 (14.0) 74.0 (10.0)* 108.4 (27.4)* 56.7 (15.7) 146.0 (104.0)y 25.1 (18.6) 25.6 (21.5)y 47.0 (65.2) 16.4 (5.9) 0.77 (0.23)* 5.2 (1.3)*
7.3 (0.9)*,z 8.9 (6.3)* 135.0 (28.8)* 161.9 (57.5)* 63.8 (13.5) 24.6 (4.3) 127.3 (13.3) 73.8 (9.5)* 107.3 (26.6)* 56.5 (17.8) 151.6 (105.8) 24.8 (19.4) 26.3 (26.2) 46.6 (61.7) 16.6 (6.2) 0.78 (0.26)*,z 5.4 (1.4)*,z
e22
diabetes research and clinical practice 95 (2012) e20–e22
biguanides [3–5], thiazolidine [6], and a-GI [7]. Renal function tests, although within normal limits, did show a significant increase in creatinine and uric acid in the present study. Regarding the effects of sitagliptin on renal function, further follow-up and observation is needed. In addition, the present study showed significant decreases in DBP and LDL cholesterol. Sitagliptin has been reported to produce significant reductions in 24-h ambulatory blood pressure in nondiabetic patients with hypertension [8]. Collectively, an antihypertensive effect of sitagliptin, although not large, may be anticipated, and in conjunction with decrease in LDL cholesterol, may play a favourable role in the prevention of macrovascular disease. Among patients’ baseline characteristics, the factor that was most related to a reduction in HbA1c after 3 months of treatment with sitagliptin was baseline HbA1c. Other significant baseline factors were higher PPG, lower BMI, and shorter duration of diabetes. These factors appear to predict response to sitagliptin when treatment is started. Further, in a meta-analysis by Esposito et al. involving 10,467 patients treated with a DPP-4 inhibitor, baseline HbA1c was the best predictor for achieving an HbA1c <7% [9]. Correlation has been found between BMI and GLP-1 secretion in diabetic patients: a lower BMI correlated with higher GLP-1 secretion [10]. The present results suggest that the correlation between the efficacy of sitagliptin and BMI could at least in part be explained by the GLP-1 response. These factors may be important clues to elucidate and understand the actions of this newly approved DPP-4 inhibitor. Our findings suggest that sitagliptin may be effective as first-line therapy for initial treatment of Japanese diabetes. Furthermore, our ongoing clinical trial will open an avenue to assess longer-term effectiveness, tolerability, and safety of sitagliptin as monotherapy and as add-on therapy in Japanese type 2 diabetic patients.
Conflict of interest The authors declare no conflict of interest.
Acknowledgments This study was supported by a grant from the Japan Diabetes Foundation. The following are ASSET-K study group investigators, Dr Akira Kanamori, Dr Kiyokazu Matoba, Dr Yasuyuki Jin, Dr Fuyuki Minagawa, Dr Mitsuo Obana, Dr Koutaro Iemitsu, Dr Syogo Ito, Dr Hikaru Amemiya, Dr Mizuki Kaneshiro, Dr Masahiko Takai, Dr Hideaki Kaneshige, Dr Kazuhiko Hoshino, Dr Masashi Ishikawa, Dr Nobuaki Minami, Dr Tetsuro Takuma, Dr Nobuo Sasai, Dr Sachio Aoyagi, Dr Takehiro Kawata, Dr Atsuko Mokubo, Dr Hiroshi Takeda, Dr Shin Honda, Dr Hideo
Machimura, Dr Tetsuya Motomiya, Dr Manabu Waseda, Dr Yukiko Miyairi. The authors would like to thank the following members of the Kanagawa Physicians Association, Dr Yoshikazu Naka, Dr. Masaaki Miyakawa and Dr. Michio Nakayama.
references
[1] Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, for Stein P for the Sitagliptin 035 Study Group. Efficiency and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:737–45. [2] Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al., Sitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract 2010;64:562–76. [3] Reasner C, Olansky L, Seck TL, Williams-Herman DE, Chen M, Terranella L, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2011;13:644– 52. [4] Goldstein BJ, Johnson J, Feinglos MN, Williams-Herman DE, Lunceford JK, for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979–87. [5] Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 2008;24:537–50. [6] Yoon KH, Shockey GR, Teng R, Golm GT, Thakkar PR, Meehan AG, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of b-cell function in patients with type 2 diabetes. Int J Clin Pract 2011;65:154–64. [7] Aoki K, Masuda K, Miyazaki T, Togashi Y, Terauchi Y. Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men. Endocr J 2010;57:667–72. [8] Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol 2008;48:592–8. [9] Esposito K, Cozzolino D, Bellastella G, Maiorino MI, Chiodini P, Ceriello A, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab 2011;13:594–603. [10] Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011;54:10–8.
Contents available at Sciverse ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Brief report
The safety, efficacy and predictors for HbA1c reduction of sitagliptin in the treatment of Japanese type 2 diabetes Hajime Maeda a,*, Akira Kubota a, Yasushi Tanaka b, Yasuo Terauchi c, Ikuro Matsuba a ASSET-K Study group a The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3F Kanagawa-ken Sogo Iryo Kaikan, 3-1 Fujimi-cho, Naka-ward, Yokohama-city, Kanagawa 231-0037, Japan b Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa 216-8511, Japan c Department of Endocrinology and Metabolism, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama-city, Kanagawa 236-0004, Japan
article info
abstract
Article history:
We evaluated the efficacy and safety of sitagliptin after 3 months’ treatment in Japanese
Received 26 September 2011
type 2 diabetic patients and examined changes in clinical factors. Baseline HbA1c, PPG, BMI,
Received in revised form
and duration of diabetes may be predictors of HbA1c reduction when using sitagliptin in
1 October 2011
Japanese type 2 diabetic patients. # 2011 Elsevier Ireland Ltd. All rights reserved.
Accepted 10 October 2011 Published on line 3 November 2011 Keywords: Dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin BMI HbA1c
1.
Introduction
This study involved a large number of Japanese type 2 diabetic patients being treated by diabetes specialists at multiple medical centers. The efficacy, safety, and the effects of patient background factors on HbA1c reduction at 3 months after starting treatment were evaluated.
2.
Methods
A total of 1332 patients were enrolled. At baseline and 3 months after starting sitagliptin, body weight, BMI, blood pressure and glycemic control-related markers were measured. Lipids, renal function, and liver function were also examined. To identify clinical factors affecting the efficacy of sitagliptin, multiple regression analyses between the change
* Corresponding author at: HEC Science Clinic, 4-1-4-102 Yokodai, Isogo-ku, Yokohama, Kanagawa 235-0045, Japan. Tel.: +81 45 831 0031; fax: +81 45 8310399. E-mail addresses: [email protected], [email protected] (H. Maeda). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.10.011
e21
diabetes research and clinical practice 95 (2012) e20–e22
Table 1 – Clinical characteristics of 1332 subjects enrolled.
in HbA1c and the patients’ baseline characteristics were performed. Safety was assessed by review of safety evaluations. All analyses were performed using SPSS for Windows. Data are presented as means SD. Statistical significance was defined as p 0.05.
3.
n Age (years) Sex (male/female) Duration of diabetes (years) Smoking (%) Drinking (%) Hypertension (%) Dyslipidemia (%) Diabetic retinopathy (%) Diabetic nephropathy (%) Diabetic neuropathy (%) Medications (%) No other OADs 1 other OAD 2 other OADs 3 other OADs
Results
The patients’ baseline demographic characteristics are shown in Table 1. 20% of all patients were treated with sitagliptin alone, 36% were treated in combination with 1 other drug, 31% were treated in combination with 2 other drugs, and 12% were treated in combination with 3 or more other drugs. With regard to changes in glycemic control after 3 months (Table 2), as compared to baseline, HbA1c decreased from 8.0% at baseline to 7.3% ( p < 0.001), and 1,5-AG increased ( p = 0.004). There were significant decreases in PPG, and in FPG ( p < 0.001). Compared with baseline, no significant weight gain was observed with sitagliptin. At 3 months, both SBP and DBP were reduced from baseline, with mean reductions of 1.2 mmHg. After 3 months, mean LDL cholesterol decreased significantly ( p < 0.001) (Table 2). On multiple regression analysis, taking HbA1c reduction at 3 months as a dependent variable, and age, baseline HbA1c, PPG, BMI, and duration of diabetes as independent variables, baseline HbA1c, baseline PPG, baseline BMI, and duration of diabetes were independently correlated with the HbA1c reduction at 3 months ( p < 0.001). As expected, baseline HbA1c was the strongest predictor. The new finding is that baseline PPG, baseline BMI and the duration of diabetes are weaker but significant predictors of change in HbA1c, showing that sitagliptin is expected to be more effective in patients with higher PPG, lower BMI or with shorter duration of diabetes. Serum creatinine and uric acid increased from baseline to 3 months ( p < 0.001) (Table 2). Adverse events were generally mild to moderate. The most common adverse event
1332 62.9 11.6 751/581 12.0 8.1 23 29 32 36 21 28 26 20 36 31 12
OAD, oral antidiabetic drug.
was hypoglycemia in 40 patients (3%); all reported events were mild. There were no serious side effects, including severe hypoglycemia.
4.
Discussion
In this multicenter collaborative study of Japanese patients treated in clinical practice by diabetes specialists, switching to sitagliptin, or using sitagliptin in combination therapy, achieved significantly improved glycemic control without weight gain. In19.3% of patients on combination therapy with a sulfonylurea, the sulfonylurea dose was reduced. There are few reports of >2 combined drugs [1], but there are several reports about the efficacy, safety, tolerability, and mechanism of action of combination therapy with sulfonylureas [2],
Table 2 – Laboratory data in type 2 DM patients at baseline, 1 month, and 3 months. n HbA1c (% in NGSP units) 1,5-AG (mg/mL) FPG (mg/dL) PPG (mg/dL) Weight (kg) BMI (kg/m2) SBP (mmHg) DBP (mmHg) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) AST (IU/L) ALT (IU/L) g-GTP (IU/L) BUN (mg/dL) Cr (mg/dL) Uric acid (mg/dL) Data are means (SD). ANOVA: vs. 0 m, p < .01. y ANOVA: vs. 0 m, p < .05. z ANOVA: vs. 1 m, p < .01. *
1029 154 165 503 936 861 663 663 438 374 494 386 393 398 360 328 345
0m 8.0 (1.1) 7.8 (5.7) 156.0 (37.2) 195.0 (72.0) 63.8 (13.4) 24.6 (4.3) 128.5 (13.9) 75.0 (10.8) 112.1 (29.1) 57.5 (17.5) 157.3 (105.6) 25.0 (16.1) 27.2 (21.0) 48.5 (61.4) 16.5 (6.7) 0.74 (0.23) 5.1 (1.3)
1m
3m *
7.6 (1.0) 8.6 (6.0)* 135.7 (29.0)* 165.7 (56.6)* 63.9 (13.5) 24.7 (4.3) 127.7 (14.0) 74.0 (10.0)* 108.4 (27.4)* 56.7 (15.7) 146.0 (104.0)y 25.1 (18.6) 25.6 (21.5)y 47.0 (65.2) 16.4 (5.9) 0.77 (0.23)* 5.2 (1.3)*
7.3 (0.9)*,z 8.9 (6.3)* 135.0 (28.8)* 161.9 (57.5)* 63.8 (13.5) 24.6 (4.3) 127.3 (13.3) 73.8 (9.5)* 107.3 (26.6)* 56.5 (17.8) 151.6 (105.8) 24.8 (19.4) 26.3 (26.2) 46.6 (61.7) 16.6 (6.2) 0.78 (0.26)*,z 5.4 (1.4)*,z
e22
diabetes research and clinical practice 95 (2012) e20–e22
biguanides [3–5], thiazolidine [6], and a-GI [7]. Renal function tests, although within normal limits, did show a significant increase in creatinine and uric acid in the present study. Regarding the effects of sitagliptin on renal function, further follow-up and observation is needed. In addition, the present study showed significant decreases in DBP and LDL cholesterol. Sitagliptin has been reported to produce significant reductions in 24-h ambulatory blood pressure in nondiabetic patients with hypertension [8]. Collectively, an antihypertensive effect of sitagliptin, although not large, may be anticipated, and in conjunction with decrease in LDL cholesterol, may play a favourable role in the prevention of macrovascular disease. Among patients’ baseline characteristics, the factor that was most related to a reduction in HbA1c after 3 months of treatment with sitagliptin was baseline HbA1c. Other significant baseline factors were higher PPG, lower BMI, and shorter duration of diabetes. These factors appear to predict response to sitagliptin when treatment is started. Further, in a meta-analysis by Esposito et al. involving 10,467 patients treated with a DPP-4 inhibitor, baseline HbA1c was the best predictor for achieving an HbA1c <7% [9]. Correlation has been found between BMI and GLP-1 secretion in diabetic patients: a lower BMI correlated with higher GLP-1 secretion [10]. The present results suggest that the correlation between the efficacy of sitagliptin and BMI could at least in part be explained by the GLP-1 response. These factors may be important clues to elucidate and understand the actions of this newly approved DPP-4 inhibitor. Our findings suggest that sitagliptin may be effective as first-line therapy for initial treatment of Japanese diabetes. Furthermore, our ongoing clinical trial will open an avenue to assess longer-term effectiveness, tolerability, and safety of sitagliptin as monotherapy and as add-on therapy in Japanese type 2 diabetic patients.
Conflict of interest The authors declare no conflict of interest.
Acknowledgments This study was supported by a grant from the Japan Diabetes Foundation. The following are ASSET-K study group investigators, Dr Akira Kanamori, Dr Kiyokazu Matoba, Dr Yasuyuki Jin, Dr Fuyuki Minagawa, Dr Mitsuo Obana, Dr Koutaro Iemitsu, Dr Syogo Ito, Dr Hikaru Amemiya, Dr Mizuki Kaneshiro, Dr Masahiko Takai, Dr Hideaki Kaneshige, Dr Kazuhiko Hoshino, Dr Masashi Ishikawa, Dr Nobuaki Minami, Dr Tetsuro Takuma, Dr Nobuo Sasai, Dr Sachio Aoyagi, Dr Takehiro Kawata, Dr Atsuko Mokubo, Dr Hiroshi Takeda, Dr Shin Honda, Dr Hideo
Machimura, Dr Tetsuya Motomiya, Dr Manabu Waseda, Dr Yukiko Miyairi. The authors would like to thank the following members of the Kanagawa Physicians Association, Dr Yoshikazu Naka, Dr. Masaaki Miyakawa and Dr. Michio Nakayama.
references
[1] Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, for Stein P for the Sitagliptin 035 Study Group. Efficiency and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:737–45. [2] Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al., Sitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract 2010;64:562–76. [3] Reasner C, Olansky L, Seck TL, Williams-Herman DE, Chen M, Terranella L, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2011;13:644– 52. [4] Goldstein BJ, Johnson J, Feinglos MN, Williams-Herman DE, Lunceford JK, for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979–87. [5] Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 2008;24:537–50. [6] Yoon KH, Shockey GR, Teng R, Golm GT, Thakkar PR, Meehan AG, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of b-cell function in patients with type 2 diabetes. Int J Clin Pract 2011;65:154–64. [7] Aoki K, Masuda K, Miyazaki T, Togashi Y, Terauchi Y. Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men. Endocr J 2010;57:667–72. [8] Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol 2008;48:592–8. [9] Esposito K, Cozzolino D, Bellastella G, Maiorino MI, Chiodini P, Ceriello A, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab 2011;13:594–603. [10] Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011;54:10–8.